DPP-4-Targeted Glycemic Control: From Incretin Regulation to Fultagliptin Innovation

The development of type 2 diabetes involves multiple mechanisms, including insulin resistance, declining pancreatic β-cell function, abnormal glucagon regulation, and an impaired incretin effect. Dipeptidyl peptidase-4 (DPP-4) rapidly processes GLP-1 and GIP and is therefore an important regulator of the effective duration of endogenous incretin activity. Fultagliptin targets DPP-4 and improves glycemic control in patients with type 2 diabetes through optimized enzyme-inhibitory potency, selectivity over closely related enzymes, and pharmacokinetic–pharmacodynamic properties.

Keywords: DPP-4; Fultagliptin; type 2 diabetes; GLP-1; GIP; incretins; DPP-4 inhibitors

1 Type 2 Diabetes and Incretin Regulation

1.1 Glucose Homeostasis and Metabolic Abnormalities in Type 2 Diabetes

(1) Normal Glucose Homeostasis

After a meal, carbohydrates are digested and absorbed as glucose, which enters the circulation. The resulting increase in blood glucose stimulates pancreatic β-cells to secrete insulin. Insulin promotes glucose uptake, utilization, and storage in skeletal muscle and adipose tissue while suppressing hepatic glycogenolysis and gluconeogenesis, thereby reducing hepatic glucose output.

Glucagon secreted by pancreatic α-cells primarily promotes hepatic glycogenolysis and gluconeogenesis during fasting or hypoglycemia, helping maintain the circulating glucose supply.

(2) Major Metabolic Defects in Type 2 Diabetes

Type 2 diabetes is not caused solely by inadequate insulin secretion. Insulin resistance reduces glucose uptake by skeletal muscle and weakens insulin-mediated suppression of hepatic glucose output. During the early stages of the disease, β-cells usually compensate by increasing insulin secretion. As the disease progresses, β-cell function gradually declines, and insulin secretion becomes insufficient to meet metabolic demands.

Inappropriate glucagon secretion can further increase hepatic glucose output, while impairment of the incretin effect weakens the postprandial insulin response.

1.2 The Incretin Effect and Its Physiological Basis

When comparable blood glucose concentrations are achieved, oral glucose generally induces a stronger insulin response than intravenous glucose. This additional insulinotropic action generated by gastrointestinal nutrient signals is known as the incretin effect.

The incretin effect is primarily mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both hormones are released in response to nutrient stimulation and enhance insulin secretion in a glucose-dependent manner. In patients with type 2 diabetes, the overall incretin effect is generally impaired, resulting in a reduced postprandial insulin response.

1.3 GLP-1- and GIP-Mediated Glycemic Regulation

(1) GLP-1

GLP-1 is primarily secreted by intestinal L cells in response to nutrient stimulation. After active GLP-1 binds to the GLP-1 receptor (GLP-1R), it enhances glucose-dependent insulin secretion and suppresses inappropriate glucagon secretion under hyperglycemic conditions. GLP-1 also participates in the regulation of gastric emptying and central food intake.

Once endogenous active GLP-1 enters the circulation, it is rapidly processed enzymatically and therefore has a short effective duration of action.

(2) GIP

GIP is primarily secreted by intestinal K cells in response to nutrient stimulation. It enhances glucose-dependent insulin secretion through the GIP receptor (GIPR). GIP and GLP-1 jointly participate in postprandial gut–islet endocrine regulation, and both hormones are rapidly processed by DPP-4.

2 Catalytic Function of DPP-4 and the Basis for Glucose-Lowering Intervention

2.1 Molecular Characteristics of DPP-4

DPP-4, also known as CD26, is a type II transmembrane serine exopeptidase that primarily functions as a homodimer. Its extracellular region contains a β-propeller domain and an α/β hydrolase domain. The catalytic region is located extracellularly and can directly encounter peptide substrates in the circulation and tissue microenvironment.

In addition to membrane-bound DPP-4, catalytically active soluble DPP-4 is present in plasma and other body fluids. In glucose metabolism, DPP-4 processes active peptides such as GLP-1 and GIP at their N termini.

2.2 Mechanism of N-Terminal Dipeptide Removal by DPP-4

DPP-4 primarily removes dipeptides from the N terminus of polypeptides and shows a strong preference for substrates containing proline or alanine at the penultimate N-terminal position. Its catalytic center contains the Ser630–Asp708–His740 catalytic triad. Glu205, Glu206, and several substrate-binding regions assist with peptide positioning and catalysis.

Because the N-terminal structures of peptide hormones frequently participate directly in receptor recognition, removal of an N-terminal dipeptide can substantially alter receptor-agonist activity.

2.3 DPP-4-Mediated Inactivation of GLP-1 and GIP

The principal forms of GLP-1 with conventional GLP-1R agonist activity are GLP-1(7-36)NH₂ and GLP-1(7-37). After DPP-4 removes the N-terminal His-Ala dipeptide, GLP-1(9-36)NH₂ or GLP-1(9-37) is formed. These truncated products have substantially reduced conventional GLP-1R agonist activity.

Intact GIP(1-42) effectively activates GIPR. After DPP-4 removes the N-terminal Tyr-Ala dipeptide, GIP(3-42) is formed, and its conventional insulinotropic activity is markedly reduced.

2.4 Glucose-Lowering Mechanism of DPP-4 Inhibition

DPP-4 inhibitors do not directly activate GLP-1R or GIPR. Instead, they restrict DPP-4 catalytic activity and reduce the inactivation of endogenous GLP-1 and GIP. Active incretin hormones released after a meal therefore persist for longer, enhancing glucose-dependent insulin secretion by β-cells and prolonging GLP-1-mediated suppression of glucagon. These effects improve both postprandial and fasting glucose control.

The insulinotropic effect of DPP-4 inhibitors is glucose dependent and decreases as blood glucose falls. Consequently, DPP-4 inhibitor monotherapy is generally associated with a low risk of hypoglycemia.

3 Drug Design and Pharmacological Properties of DPP-4 Inhibitors

3.1 Pharmacological Differences Between DPP-4 Inhibitors and GLP-1R Agonists

DPP-4 inhibitors and GLP-1R agonists both influence GLP-1-related metabolic regulation, but their initial mechanisms of action differ. DPP-4 inhibitors reduce the inactivation of endogenous GLP-1 and GIP, and their effects are therefore limited by the body’s own incretin secretion. GLP-1R agonists, in contrast, directly provide a pharmacological receptor-activation signal.

Comparison Parameter	DPP-4 Inhibitors	GLP-1R Agonists
Primary mechanism	Reduce the inactivation of endogenous GLP-1 and GIP	Directly activate GLP-1R
GIP pathway	Also preserve endogenous GIP	Generally do not depend on GIPR
Major drug form	Oral small molecules	Primarily peptide drugs, with some oral formulations available
Degree of GLP-1R stimulation	Limited by endogenous GLP-1 secretion	Can produce relatively strong pharmacological receptor activation
Effect on body weight	Generally weight neutral	Most produce varying degrees of weight loss
Risk of hypoglycemia as monotherapy	Low	Generally low

3.2 Binding Modes of DPP-4 Inhibitors

DPP-4 inhibitors can occupy the enzyme’s active region through different chemical binding modes. Some inhibitors, represented by vildagliptin, form reversible covalent interactions with the catalytic Ser630 residue and thereby restrict hydrolysis of natural substrates.

Another class, represented by sitagliptin, primarily achieves noncovalent binding through hydrogen bonds, ionic interactions, hydrophobic interactions, and aromatic interactions.

3.3 Selectivity Over DPP8/DPP9 and Drug-Like Properties

Related peptidases such as DPP8 and DPP9 share certain structural and substrate-recognition features with DPP-4, but they have different cellular localizations and physiological functions. If a candidate compound substantially inhibits these related enzymes while inhibiting DPP-4, off-target effects and safety evaluation may become more complex.

An in vitro IC₅₀ reflects enzyme-inhibitory potency under specific experimental conditions. A candidate entering clinical development must also exhibit appropriate oral absorption, systemic exposure, metabolic stability, clearance characteristics, and duration of pharmacological action.

4 Molecular Innovation and Sustained Pharmacological Activity of Fultagliptin

4.1 Pharmacological Positioning of Fultagliptin

Fultagliptin is an orally administered small-molecule DPP-4 inhibitor. Its marketed drug form is Fultagliptin benzoate, which is primarily used for glycemic control in patients with type 2 diabetes.

By inhibiting DPP-4-mediated inactivation of GLP-1 and GIP, Fultagliptin prolongs the effective activity of endogenous incretin hormones and enhances glucose-dependent insulin secretion.

4.2 DPP-4 Inhibitory Potency and Selectivity Over Related Enzymes

Fultagliptin exhibits nanomolar-level in vitro inhibitory activity against DPP-4. It can therefore restrict DPP-4 catalytic function at relatively low concentrations and reduce the inactivation of GLP-1 and GIP.

Its selectivity assessment also includes closely related enzymes such as DPP8 and DPP9. Relatively weak inhibition of these enzymes reduces interference with peptidases other than DPP-4.

4.3 Pharmacokinetic–Pharmacodynamic Characteristics of Fultagliptin

Drug absorption, systemic exposure, and clearance determine how long an effective drug concentration is maintained in vivo. The association and dissociation characteristics between a drug and DPP-4 also affect recovery of enzyme activity. In vitro inhibitory potency alone therefore cannot predict the duration of action in vivo.

Following oral administration, Fultagliptin achieves effective drug exposure and sustains DPP-4 inhibition for an extended period. This reduces the rapid processing of postprandial GLP-1 and GIP and provides a pharmacodynamic basis for once-daily administration.

5 Clinical Validation and Therapeutic Positioning of Fultagliptin

5.1 Monotherapy

Phase III studies of Fultagliptin monotherapy primarily enrolled patients with type 2 diabetes whose glycemic control remained inadequate after diet and exercise interventions. Treatment reduced HbA1c and improved fasting and postprandial glucose levels.

Alogliptin was used as an active comparator, and Fultagliptin met the predefined noninferiority criterion for the primary glucose-lowering endpoint.

5.2 Combination Therapy With Metformin

Metformin primarily reduces hepatic glucose output and improves overall glucose metabolism. Fultagliptin enhances glucose-dependent islet responses by reducing the inactivation of GLP-1 and GIP.

In patients receiving stable metformin therapy whose HbA1c remained above the target range, the addition of Fultagliptin further improved HbA1c and related glycemic parameters.

5.3 Pharmacological Characteristics and Boundaries of Clinical Evidence

Fultagliptin exhibits the glucose-dependent pharmacological characteristics typical of DPP-4 inhibitors. The risk of hypoglycemia is generally low when it is used as monotherapy, and its overall effect on body weight is neutral. As an orally administered small molecule, its sustained DPP-4 inhibition supports once-daily dosing.

The effect of Fultagliptin on the GLP-1 pathway results from reduced inactivation of endogenous hormones and is therefore clearly different from the direct activation produced by GLP-1R agonists. Current clinical evidence primarily supports its ability to improve glycemic control. Independent cardiovascular or renal protection and clinically substantial weight-loss effects would require support from dedicated clinical-outcome studies.

6 Products

6.1 Products for DPP-4 Target and Enzyme-Activity Research

Catalog #	Product Name	Grade and Purity	Function and Research Application
D755313	Dipeptidyl Peptidase IV human	Bioactive, Recombinant, EnzymoPure™, His Tag, ≥95%(SDS-PAGE), ≥4000 U/μg protein, Protein concentration: See COA, Expressed in HEK293	Provides a DPP-IV enzyme source for enzyme-kinetic studies and inhibitor-potency evaluation
Ab100398	Recombinant DPP4 Antibody	Recombinant, ExactAb™, validated, see COA	Specifically recognizes DPP4; used for target-protein detection and validation of experimental interventions
EJ1512632	Mouse Dipeptidyl Peptidase Ⅳ (DPPⅣ) ELISA Kit	BioReagent	Quantifies mouse DPPⅣ protein; used to evaluate target levels in animal models
G342212	H-Gly-Pro-AMC · HBr	≥95%	Fluorogenic substrate for DPP-related enzymes; used in enzyme-activity assays and inhibitor screening
G1496620	Gly-Pro-AMC hydrobromide	Moligand™, 10 mM in DMSO	Preformulated fluorogenic substrate used in DPP enzyme-activity assays and concentration-gradient studies
A109916	7-Amino-4-methylcoumarin	Laser grade, ≥99% (HPLC)	Fluorescent-product standard used for calibration curves and quantitative enzyme-activity analysis
A1499659	7-Amino-4-methylcoumarin	Moligand™, 10 mM in DMSO	Preformulated AMC standard used for fluorescence-assay calibration
rp165443	Recombinant Human DPPII/QPP/DPP7 Protein	Animal free, carrier free, bioactive, ActiBioPure™, His tag, ≥95% (SDS-PAGE)	Provides a DPP7 enzyme source for selectivity comparisons involving related peptidases

6.2 DPP-4 Inhibitors and Pharmacological Research Products

Catalog #	Product Name	Grade and Purity	Function and Research Application
F1441928	Fotagliptin	—	DPP-4 inhibitor and the core research compound discussed in this article; used for studies of DPP-4 inhibitory activity, mechanism of action, and pharmacological effects
F1495517	Fotagliptin benzoate	Moligand™, 10 mM in DMSO	Pre-prepared solution of Fotagliptin benzoate for DPP-4 inhibition, dose–response, and pharmacological intervention studies
F1441944	Fotagliptin benzoate	≥99%	High-purity Fotagliptin benzoate for studies of DPP-4 inhibitory activity, pharmacological effects, and related mechanisms
S176594	sitagliptin	Moligand™, ≥97%	Inhibits DPP-4; used as a reference compound in class-comparison and mechanism studies
S304295	Sitagliptin phosphate	≥98%	Inhibits DPP-4; used in pharmacological interventions and concentration–response studies
L127331	Linagliptin	Moligand™, ≥99%	High-affinity DPP-4 inhibitor used in enzyme-inhibition and pharmacological-effect comparisons
L407945	Linagliptin (BI-1356)	Moligand™, 10mM in DMSO	Preformulated inhibitor solution used in cellular and enzymatic studies
A126201	Alogliptin	Moligand™, ≥99%	Selectively inhibits DPP-4; used as a reference drug for comparison with Fultagliptin
V125454	Vildagliptin (LAF-237)	Moligand™, ≥99%	Reversibly inhibits DPP-4; used in binding-mode and pharmacological-effect studies
D646861	DPP-IV-IN-1	≥98%	DPP-IV inhibitor tool compound used to validate target-dependent effects

6.3 GLP-1, GIP, and Glucose-Metabolism Research Products

Catalog #	Product Name	Grade and Purity	Function and Research Application
G659462	GLP-1(7-36), amide TFA	≥98%	Active GLP-1 ligand used in receptor-signaling and DPP-4-processing studies
S1432892	(Ser8)-GLP-1 (7-36) amide, human	≥99%	GLP-1 analog peptide used to compare peptide stability and receptor activity
G658840	GLP-1(7-36)-Lys (Biotin), amide, human	≥98%	Biotin-labeled ligand used in GLP-1R-binding and localization studies
G409312	GLP-1 (9-36) amide TFA	≥98%	Truncated GLP-1 form used to investigate the products and functional consequences of DPP-4 processing
G658910	GIP, human TFA	≥99%	GIP ligand and DPP-4 substrate used in GIP-stability studies
EJ1515661	Human Glucagon Like Peptide 1 (GLP-1) ELISA Kit	BioReagent	Quantifies human GLP-1; used to evaluate incretin levels
EJ1514147	Human Gastric Inhibitory Polypeptide (GIP) ELISA Kit	BioReagent	Quantifies human GIP; used in DPP-4–GIP metabolism studies
EJ1515539	Mouse Glucagon Like Peptide 1 (GLP-1) ELISA Kit	BioReagent	Quantifies mouse GLP-1; used in animal-model studies
EJ1515550	Mouse Hypersensitive Insulin (hs-INS) ELISA Kit	BioReagent	Quantifies mouse insulin; used to evaluate pancreatic islet secretory function
EJ1515425	Rat Insulin (INS) ELISA Kit	BioReagent	Quantifies rat insulin; used to evaluate pancreatic islet function
G1527306	Glucose Content Assay Kit (NADPH Rate, UV Colorimetric Method)	BioReagent	Quantifies glucose; used to evaluate glucose-lowering effects and metabolic endpoints
G1493294	GLP-1R Antagonist 1	Moligand™, 10 mM in DMSO	Inhibits GLP-1R signaling; used to validate dependence on downstream receptor pathways

Fultagliptin prolongs the effective activity of endogenous GLP-1 and GIP by inhibiting DPP-4. Its development has focused on target-enzyme potency, selectivity over closely related enzymes, and sustained pharmacological activity.

Major Abbreviations

Abbreviation	Full Name	Definition
DPP-4	Dipeptidyl Peptidase-4	An N-terminal dipeptide-cleaving serine peptidase
CD26	Cluster of Differentiation 26	Alternative designation for DPP-4
GLP-1	Glucagon-Like Peptide-1	An incretin hormone that enhances glucose-dependent insulin secretion
GIP	Glucose-Dependent Insulinotropic Polypeptide	An incretin hormone released in response to nutrient stimulation
GLP-1R	Glucagon-Like Peptide-1 Receptor	Receptor that mediates the metabolic effects of GLP-1
GIPR	Glucose-Dependent Insulinotropic Polypeptide Receptor	Receptor that mediates the insulinotropic effects of GIP
T2DM	Type 2 Diabetes Mellitus	A metabolic disease characterized by insulin resistance and progressive β-cell dysfunction
HbA1c	Glycated Hemoglobin A1c	A marker of long-term glycemic control
IC₅₀	Half-Maximal Inhibitory Concentration	Concentration required to inhibit 50% of the measured activity
PK	Pharmacokinetics	Drug absorption, distribution, metabolism, and elimination
PD	Pharmacodynamics	Relationship between drug exposure and biological effects
AMC	7-Amino-4-Methylcoumarin	Fluorescent product used in peptide-substrate enzyme assays

References

[1] Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–1705.

[2] Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019.

[3] Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011;13(1):7–18.

[4] Wu M, Li QQ, Zhang H, et al. Safety, pharmacokinetics, and pharmacodynamics of a dipeptidyl peptidase-4 inhibitor: a randomized, double-blinded, placebo-controlled daily administration of Fotagliptin benzoate for 14 days for type 2 diabetes mellitus. Clin Pharmacol Drug Dev. 2021;10(6):660–668.

[5] Ding Y, Zhang H, Li C, et al. Safety and pharmacokinetic interaction between Fotagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin in healthy subjects. Expert Opin Drug Metab Toxicol. 2021;17(6):725–731.

[6] Xu M, Sun K, Xu W, et al. Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial. BMC Med. 2023;21(1):388.

[7] Yu N, Xu W, Guo X, et al. Fotagliptin add-on therapy to metformin in patients with uncontrolled type 2 diabetes: a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Diabetes Obes Metab. 2025;27(7):3933–3942.

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